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WO2018141276A1 - 布瓦西坦中间体的晶型a及其制备方法和布瓦西坦的晶型c及其制备方法 - Google Patents

布瓦西坦中间体的晶型a及其制备方法和布瓦西坦的晶型c及其制备方法 Download PDF

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WO2018141276A1
WO2018141276A1 PCT/CN2018/075177 CN2018075177W WO2018141276A1 WO 2018141276 A1 WO2018141276 A1 WO 2018141276A1 CN 2018075177 W CN2018075177 W CN 2018075177W WO 2018141276 A1 WO2018141276 A1 WO 2018141276A1
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solvent
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李丕旭
王鹏
魏强
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Suzhou Pengxu Pharmaceutical Technology Co Ltd
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Suzhou Pengxu Pharmaceutical Technology Co Ltd
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Priority claimed from CN201710118467.XA external-priority patent/CN107056643A/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom

Definitions

  • the invention relates to the field of chemical medicine, in particular to a crystalline form A of a basixamine intermediate, a preparation method thereof and a crystalline form C of bovistam and a preparation method thereof.
  • Epilepsy is a common disease of the nervous system. The incidence rate in the population is 0.6% to 1.1%, and 60% to 70% of patients still have seizures when taking anti-epileptic drugs, causing some patients to stop taking drugs themselves. At present, there are about 6 million epilepsy patients in China, and 650,000 to 700,000 new epilepsy patients each year, and about 25% are refractory epilepsy. Although the current diagnosis and treatment of epilepsy has made great progress, the number of patients with refractory epilepsy is increasing.
  • Generalized refractory epilepsy refers to the use of current anti-epileptic drugs (AEDs) to treat epilepsy and epilepsy syndrome that cannot be terminated or has been clinically proven to be refractory.
  • AEDs anti-epileptic drugs
  • Bovasitan English name: Brivaracetam
  • the structural formula is: Bovasistatin is a novel high-affinity synaptophysin 2A ligand that inhibits neuronal voltage-dependent sodium channels and is used to treat partial seizures of refractory epilepsy.
  • Phase II, phase III clinical trials of bovistam have a good effect. The incidence of major adverse events was similar to that of the placebo group, with mild to moderate fatigue, headache, nasopharyngitis, nausea, lethargy, and dizziness. No patients discontinued treatment due to adverse events.
  • the results indicate that bovistam tablets are effective and well tolerated in the adjuvant treatment of patients with refractory epilepsy with a prevalence of 16 to 65 years of age.
  • bovistam is a third-generation anti-epileptic drug with very good prospects after levetiracetam. It was approved for listing in the United States in February 2016.
  • Chiral HPLC purity separation requires expensive equipment and consumables and is not suitable for large scale production.
  • chiral HPLC purity separation if the yield is to be increased and the cost is reduced, it will inevitably lead to the collection of more isomer components, and the quality will be reduced.
  • the presence of a large amount of chiral impurities may cause adverse drug reactions and influence.
  • the safety of the drug In addition, the patent CN104892483A reports a method of asymmetric catalytic hydrogenation, but in which an expensive chiral ligand is used, the route is uneconomical.
  • CN106279074A, CN106365986A, CN106432030A and CN105646319A report the synthesis of bovistam from a chiral raw material which is readily available at low cost, the route does not involve expensive chiral catalysts or ligands, and does not require chiral HPLC purity separation and purification of the final product, Among them, compound I is an intermediate for the synthesis of bovistam, which is essential for the successful synthesis of high purity, high chiral purity of bovistam.
  • the structural formula of Compound I is:
  • the polymorph of a drug means that two or more different crystalline form states exist in the drug
  • the polymorph of the compound means that two or more different crystalline form states exist in the compound.
  • Polymorphism is widespread in drugs and organic compounds. Different crystal forms of the same drug or the same compound have significant differences in solubility, melting point, density, stability, etc., thereby affecting the stability and uniformity of the drug or compound to varying degrees, and affecting the drug for the drug. Bioavailability, efficacy and safety.
  • the research on the crystal form and purification process of the drug intermediate compound is beneficial to reduce the production cost of the active ingredient of the drug, improve the quality of the active ingredient of the drug, and ensure the quality and safety of the drug preparation. Therefore, in drug development, comprehensive systematic polymorph screening of drugs and drug intermediates, and selection of the most suitable crystal form, is one of the important research contents that cannot be ignored.
  • the invention provides a new crystal form of the bovastatin intermediate compound I, named as the crystal form A, and the crystal form A provided by the invention has the significant improvement effect on the purification of the compound I, and has good stability and process development.
  • the preparation method of crystal form A is simple and low in cost, and has important value for the production, purification and quality control of compound I, and is essential for obtaining bovastatin bulk drug of high purity and high chiral purity. .
  • the invention also provides a new crystal form of basistatin, named as crystal form C, and the crystal form C provided by the invention has favorable properties such as good stability, process development and easy handling, and the preparation method is simple and the cost is Low cost and valuable for the development and formulation optimization of bovistam.
  • the present invention adopts the following technical solutions:
  • the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 17.4 ° ⁇ 0.2 °, 25.5 ° ⁇ 0.2 °, 28.1 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 14.0 ° ⁇ 0.2 °, 19.1 ° ⁇ 0.2 °, and 36.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is also 2theta value of 17.4 ° ⁇ 0.2 °, 25.5 ° ⁇ 0.2 °, 28.1 ° ⁇ 0.2 °, 14.0 ° ⁇ 0.2 °, 19.1 ° ⁇ 0.2 ° , with characteristic peaks at 36.5 ° ⁇ 0.2 °.
  • its X-ray powder diffraction pattern is substantially identical to that of FIG.
  • the content of the enantiomer and the diastereomer are not more than 2.5%.
  • Diastereomers of Compound I include those represented by the following structural formula:
  • the content of both the enantiomeric and diastereomers is not more than 1.0%.
  • the content of both the enantiomeric and diastereomers is not more than 0.5%.
  • the content of both enantiomers and diastereomers is not more than 0.15%.
  • Another object of the present invention is to provide a process for the preparation of Form A of Compound I, which comprises adding a powder of Compound I to a mixed system of one or more solvents for crystallization.
  • the crystallization method includes a suspension stirring method, a heating and cooling method, a volatilization method or an anti-solvent addition method.
  • the solvent is selected from the group consisting of water, an alcohol solvent, an ether solvent, a ketone solvent, an ester solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrile solvent, a nitroalkane solvent, and an aliphatic hydrocarbon solvent.
  • the solvent is selected from the group consisting of water, an alcohol solvent, an ether solvent, a ketone solvent, an ester solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrile solvent, a nitroalkane solvent, and an aliphatic hydrocarbon solvent.
  • the solvent is selected from the group consisting of water, an alcohol solvent, an ether solvent, a ketone solvent, an ester solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrile solvent, a nitroalkane solvent, and an aliphatic hydrocarbon solvent.
  • the solvent is a mixed system of an ether solvent and an aliphatic hydrocarbon solvent, preferably a mixed system of tetrahydrofuran and n-heptane.
  • the method of crystallization is a heating and cooling method, and the specific process comprises: adding the compound I powder to the first solvent, raising the temperature to 50 to 60 ° C, stirring, and then adding the second solvent. Cooling to 0-10 ° C, filtration, the obtained filter cake is dried to obtain the crystal form A, wherein the first solvent is water, alcohols, ethers, ketones, esters, aromatic hydrocarbons, halogen a mixed system of one or more of a hydrocarbon, a nitrile, a nitroalkane, an aliphatic hydrocarbon solvent; the second solvent is water, an alcohol, an ether, a ketone, an ester, an aromatic hydrocarbon, a halogen A mixed system of one or more of a hydrocarbon, a nitrile, a nitroalkane, and an aliphatic hydrocarbon solvent.
  • the first solvent is water, alcohols, ethers, ketones, esters, aromatic hydrocarbons, halogen a mixed system of one or more of a
  • the first solvent and the second solvent are different solvents.
  • the first solvent is a mixed system of one or more of an ether, a ketone, and a nitrile; and the second solvent is an aliphatic hydrocarbon, an ether, or one of water or Several hybrid systems.
  • the first solvent is a mixed system of one or more of tetrahydrofuran, acetone, acetonitrile;
  • the second solvent is n-heptane, methylcyclohexane, methyl t-butyl A mixed system of one or more of ether and water.
  • a third object of the present invention is to provide a use of the crystalline form A of the compound I as an intermediate for the synthesis of bovistam.
  • a fourth object of the present invention is to provide a crystalline form C of bovistam with an X-ray powder diffraction pattern having a value of 15.7 ° ⁇ 0.2 °, 17.4 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 26.9 °. There is a characteristic peak at ⁇ 0.2°.
  • the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 8.9 ° ⁇ 0.2 °, 19.2 ° ⁇ 0.2 °, and 21.6 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 10.0 ° ⁇ 0.2 °, 15.0 ° ⁇ 0.2 °, and 25.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is also 2theta values of 8.9 ° ⁇ 0.2 °, 19.2 ° ⁇ 0.2 °, 21.6 ° ⁇ 0.2 °, 10.0 ° ⁇ 0.2 °, 15.0 ° ⁇ 0.2 ° , with characteristic peaks at 25.0 ° ⁇ 0.2 °.
  • its X-ray powder diffraction pattern is substantially identical to that of FIG.
  • a fifth object of the present invention is to provide a process for preparing bovistam form C, which comprises adding bovistam powder to a mixed system of one or more solvents for crystallization.
  • the method of crystallization includes a suspension stirring method, a heating and cooling method, a volatilization method or an anti-solvent addition method.
  • the solvent is one selected from the group consisting of an alcohol solvent, an ether solvent, a ketone solvent, an ester solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, a nitrile solvent, a nitroalkane solvent, and an aliphatic hydrocarbon solvent. Mixed system of one kind or several kinds.
  • the solvent is methyl tert-butyl ether.
  • a sixth object of the present invention is to provide a pharmaceutical composition comprising an effective amount of said crystalline form C of bovistam and a pharmaceutically acceptable excipient.
  • a seventh object of the present invention is to provide the use of said crystalline form C of bovistam or said pharmaceutical composition for the preparation of a pharmaceutical preparation for the treatment of epilepsy.
  • the new crystalline form (crystal form A) of the bovastatin intermediate compound I provided by the invention has remarkable purification effect and good stability;
  • the crystallization method of the crystal form A provided by the present invention can effectively control the enantiomeric and diastereomers in the compound I to 2.5% or less, further, 1.0% or less, further, 0.5% or less, further, 0.15. %the following;
  • the high chiral purity compound I obtained by the crystallization method provided by the invention can be used to produce bovastatin with high chiral purity, improve the chiral purity of the final active ingredient of the drug, and reduce the potential adverse reaction caused by chiral impurities. Thereby improving the safety of the drug;
  • the preparation method of the crystal form A provided by the invention is simple and reproducible, the solvent is not easy to remain, and the process is controllable, and is suitable for direct use in industrial production.
  • the novel crystalline form of Bevastatin (Form C) provided by the present invention is better than the crystalline forms A and B of Bovaciltam disclosed by U.S. Patent No. 6,784,197. Stability, suitable for long-term storage and industrial production, to provide more and better choice for the subsequent development of drugs.
  • the crystallization method of the crystal form C provided by the invention can effectively control the impurities to be less than 0.10%;
  • the crystallization of the process provided by the patent US 6,784,197 is carried out using isopropyl ether, which presents a potential hazard in industrial scale-up.
  • the preparation method of the crystal form C provided by the invention is simple and reproducible, avoids the use of dangerous solvents, the solvent is not easy to remain, and the process is controllable, and is suitable for direct use in industrial production.
  • Example 2 is a TGA chart and a DSC chart overlay of Compound I Form A of Example 1.
  • Figure 3 is an XRPD pattern of the Bovaxitan Form C.
  • test methods described are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the compound I is prepared by the method of WO2016191435.
  • the X-ray powder diffraction pattern of the present invention was collected on a PANalytical Empyrean X-ray diffraction powder diffractometer.
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q200.
  • the method parameters of the differential scanning calorimetry (DSC) of the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows:

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Abstract

本发明公开了一种布瓦西坦中间体化合物I的新晶型及其制备方法和布瓦西坦的新晶型及其制备方法，具体地为化合物I的晶型A，布瓦西坦的晶型C。本发明提供晶型A有良好的稳定性、工艺可开发和易处理等有利性能，且制备方法简单，成本低廉，对该药物活性成分的生产、纯化和品质控制具有重要价值。本发明提供的晶型C有良好的稳定性、工艺可开发和易处理等有利性能，且制备方法简单，成本低廉，对未来该药物的优化和开发具有重要价值。

Description

布瓦西坦中间体的晶型A及其制备方法和布瓦西坦的晶型C及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及布瓦西坦中间体的晶型A及其制备方法和布瓦西坦的晶型C及其制备方法。
背景技术
癫痫是神经系统的常见病，在人群中的发病率为0.6％～1.1％，其中60％～70％的患者在服用抗癫痫药物时仍会发作，导致一部分患者自行停止药物治疗。目前我国有约600万以上的癫痫患者，每年新发癫痫患者65万～70万，大约25％为难治性癫痫。虽然目前癫痫的诊疗取得了很大的进展，但难治性癫痫患者的数量却在日益增多。广义难治性癫痫是指使用目前的抗癫痫药物(AEDs)规范治疗，不能终止其发作或已被临床证实是难治的癫痫及癫痫综合征。
布瓦西坦，英文名称为：Brivaracetam，结构式为：
Figure PCTCN2018075177-appb-000001
布瓦西坦是一个新型的高亲和力的突触囊泡蛋白2A配体，可抑制神经元电压依赖性钠通道，用于治疗难治性癫痫部分性发作。布瓦西坦的II期，III期临床试验皆有较好的疗效。布瓦西坦的主要不良事件的发生率与安慰剂组的发生率相似，均为轻度至中度的疲劳、头痛、鼻咽炎、恶心、嗜睡和头晕。无患者因不良事件而中断治疗。结果表明布瓦西坦片在辅助治疗年龄为16～65岁的难治性癫痫部分性发作患者中是有效的且耐受性良好。总体而言，布瓦西坦是继左乙拉西坦之后的一个前景十分良好的第三代抗癫痫类药物。已于2016年2月在美国获批上市。
目前为止，关于布瓦西坦晶型专利国内还未见报道。国外仅有原研专利US 6,784,197，公布晶型A的X射线粉末衍射图在2theta值为8.8，9.8，14.9，15.0，17.0，17.1，21.2，21.4，24.8；晶型B的X射线粉末衍射图在2theta值为6.50，11.25，19.22，23.44，28.47，29.94。
而关于布瓦西坦合成的国内专利还未见报道。国外相关专利报道也不多，诸如专利US 6,784,197,US 7,629,474，US 8,957,226，US 8,338,621，US 8,076,493及其相关专利报道了布瓦西坦的合成，其中US 6,784,197,US 7,629,474报道了一些合成路线，这些合成路线所存在的问题主要集中在，工艺路线不能选择性的合成目标手性分子，存在需要柱层析纯化、 手性高效液相色谱纯化等不利于工业放大生产的操作方法。手性HPLC纯度分离需要昂贵的设备和耗材，不适合大规模生产。另外在手性HPLC纯度分离中，如果要提高收率，降低成本，必然会导致收集较多的异构体成分，品质会因此而降低，大量手性杂质的存在可能会导致药物不良反应，影响药物的安全性。另外，专利CN104892483A报道了不对称催化氢化的方法，但是其中使用了昂贵的手性配体，路线不经济。CN106279074A、CN106365986A、CN106432030A和CN105646319A报道了一种通过低价易得的手性原料合成布瓦西坦，路线不涉及昂贵的手性催化剂或配体，也不需要手性HPLC纯度分离纯化最终产品，其中化合物I是合成布瓦西坦的一个中间体，这个中间体对于成功合成高纯度、高手性纯度的布瓦西坦至关重要。化合物I的结构式为：
Figure PCTCN2018075177-appb-000002
药物的多晶型是指在药物中存在有两种或两种以上的不同晶型物质状态，化合物的多晶型是指在化合物中存在有两种或两种以上的不同晶型物质状态。多晶型现象在药物和有机化合物中广泛存在。同一药物或同一化合物的不同晶型在溶解度、熔点、密度、稳定性等方面有显著的差异，从而不同程度的影响药物或化合物的稳定性和均一性，对于药物来说，还会影响药物的生物利用度、疗效和安全性。此外，药物中间体化合物的晶型与纯化工艺的研究有利于降低药物活性成分的生产成本，提高药物活性成分的品质，保证药物制剂的品质与安全性。因此，药物研发中，对药物以及药物中间体进行全面系统的多晶型筛选，选择最合适开发的晶型，是不可忽视的重要研究内容之一。
发明内容
本发明提供一种布瓦西坦中间体化合物I的新晶型，命名为晶型A，本发明提供的晶型A对化合物I的提纯效果显著提升，且有良好的稳定性、工艺可开发和易处理等有利性能，晶型A的制备方法简单，成本低廉，对化合物I的生产、纯化和品质控制具有重要价值，对于得到高纯度和高手性纯度的布瓦西坦原料药至关重要。
本发明还提供一种布瓦西坦的新晶型，命名为晶型C，本发明提供的晶型C有良好的稳定性、工艺可开发和易处理等有利性能，且制备方法简单，成本低廉，对布瓦西坦的开发和剂型优化具有重要价值。
为实现上述目的，本发明采用如下技术方案：
本发明的一个目的是提供一种化合物I的晶型A，其X射线粉末衍射图在2theta值为 7.9°±0.2°，15.7°±0.2°，21.7°±0.2°,28.6°±0.2°处具有特征峰，
其中化合物I的结构为，
Figure PCTCN2018075177-appb-000003
进一步地，其X射线粉末衍射图还在2theta值为17.4°±0.2°，25.5°±0.2°，28.1°±0.2°处具有特征峰。
进一步地，其X射线粉末衍射图还在2theta值为14.0°±0.2°，19.1°±0.2°，36.5°±0.2°处具有特征峰。
根据本发明的一个具体且优选方面，其X射线粉末衍射图还在2theta值为17.4°±0.2°，25.5°±0.2°，28.1°±0.2°，14.0°±0.2°，19.1°±0.2°，36.5°±0.2°处具有特征峰。
在根据该方案的一个具体实施方式中，其X射线粉末衍射图基本与图1一致。
进一步地，其纯度大于98.0％。
更进一步地，其纯度大于99.0％。
再进一步地，其纯度大于99.5％。
进一步地，所述化合物I中，其对映及非对映异构体的含量均不大于2.5％，
其中化合物I的对映异构体的结构为
Figure PCTCN2018075177-appb-000004
化合物I的非对映异构体包括如下结构式所示物质：
Figure PCTCN2018075177-appb-000005
更进一步地，其对映和非对映异构体的含量均不大于1.0％。
再进一步地，其对映和非对映异构体的含量均不大于0.5％。
最优选地，其对映和非对映异构体的含量均不大于0.15％。
本发明的另一个目的是提供一种化合物I的晶型A的制备方法，包括将化合物I粉末加入到一种或多种溶剂的混合体系中，进行结晶得到。
进一步地，所述结晶方法包括混悬搅拌法，加热降温法，挥发法或反溶剂添加法。
进一步地，所述溶剂为选自水，醇类溶剂，醚类溶剂，酮类溶剂，酯类溶剂，芳香烃溶剂，卤代烃溶剂，腈类溶剂，硝基烷烃溶剂，脂肪烃类溶剂中的一种或几种。
更进一步地，所述溶剂是醚类溶剂与脂肪烃类溶剂的混合体系，优选四氢呋喃与正庚烷的混合体系。
根据本发明的一个具体且优选方面，所述结晶的方法为加热降温法，具体实施过程包括：将化合物I粉末加入到第一溶剂中，升温至50～60℃，搅拌，然后加入第二溶剂，降温至0～10℃，过滤，所得滤饼经干燥得到所述的晶型A，其中，所述的第一溶剂为水，醇类，醚类，酮类，酯类，芳香烃，卤代烃，腈类，硝基烷烃，脂肪烃类溶剂中的一种或几种的混合体系；所述的第二溶剂为水，醇类，醚类，酮类，酯类，芳香烃，卤代烃，腈类，硝基烷烃，脂肪烃类溶剂中的一种或几种的混合体系。
进一步优选地，所述的第一溶剂和所述的第二溶剂为不同的溶剂。
再进一步优选地，所述的第一溶剂为醚类、酮类、腈类中的一种或几种的混合体系；所述的第二溶剂为脂肪烃类、醚类、水中的一种或几种的混合体系。
更为优选地，所述的第一溶剂为四氢呋喃、丙酮、乙腈中的一种或几种的混合体系；所述的第二溶剂为正庚烷、甲基环己烷、甲基叔丁基醚、水中的一种或几种的混合体系。
本发明的第三个目的是提供一种所述的化合物I的晶型A作为中间体合成布瓦西坦的用途。
本发明的第四个目的是提供一种布瓦西坦的晶型C，其X射线粉末衍射图在2theta值为15.7°±0.2°,17.4°±0.2°，17.9°±0.2°,26.9°±0.2°处具有特征峰。
进一步地，其X射线粉末衍射图还在2theta值为8.9°±0.2°,19.2°±0.2°，21.6°±0.2°处具有特征峰。
进一步地，其X射线粉末衍射图还在2theta值为10.0°±0.2°,15.0°±0.2°，25.0°±0.2°处具有特征峰。
根据本发明的一个具体且优选方面，其X射线粉末衍射图还在2theta值为8.9°±0.2°,19.2°±0.2°，21.6°±0.2°，10.0°±0.2°,15.0°±0.2°，25.0°±0.2°处具有特征峰。
在根据该方案的一个具体实施方式中，其X射线粉末衍射图基本上与图1一致。
本发明的第五个目的是提供一种布瓦西坦晶型C的制备方法，包括将布瓦西坦粉末加入到一种或多种溶剂的混合体系中，进行结晶得到。
进一步地，所述结晶的方法包括混悬搅拌法，加热降温法，挥发法或反溶剂添加法。
进一步地，所述溶剂为选自醇类溶剂，醚类溶剂，酮类溶剂，酯类溶剂，芳香烃溶剂，卤代烃溶剂，腈类溶剂，硝基烷烃溶剂，脂肪烃类溶剂中的一种或几种的混合体系。
更进一步地，所述溶剂是甲基叔丁基醚。
本发明的第六个目的是提供一种药用组合物，所述药用组合物包含有效量的所述的布瓦西坦的晶型C及药学上可接受的赋形剂。
本发明的第七个目的是提供所述的布瓦西坦的晶型C或所述的药物组合物用于制备治疗癫痫的药物制剂的用途。
本发明的有益效果为：
本发明提供的布瓦西坦中间体化合物I的新晶型(晶型A)的提纯效果显著，且有较好的稳定性；
本发明提供的晶型A的结晶方法可以有效的将化合物I中对映和非对映异构体控制在2.5％以下，进一步的，1.0％以下，进一步的，0.5％以下，进一步的，0.15％以下；
本发明提供的结晶方法得到的高手性纯度的化合物I可以用来生产高手性纯度的布瓦西坦，提高最终药物有效成分的手性纯度，降低因为手性杂质带来的潜在的不良反应，从而提高药物的安全性；
本发明提供的晶型A的制备方法简单且重复性好，溶剂不易残留，且过程可控，适合直接用于工业化生产。
本发明提供的布瓦西坦的新晶型(晶型C)与UCB公司在专利US 6,784,197中公开的布瓦西坦的晶型A和晶型B两种晶型相比，具有更好的稳定性，适合长期存储和工业化生产的，为药物的后续开发提供更多更好的选择。
本发明提供的晶型C的结晶方法可以有效的将杂质控制在0.10％以下；
专利US 6,784,197提供的方法结晶采用异丙醚进行，在工业放大中存在潜在的危险性。而本发明提供的晶型C的制备方法简单且重复性好，避免使用危险溶剂，溶剂不易残留，且过程可控，适合直接用于工业化生产。
附图说明
图1为实施例1的化合物I晶型A的XRPD图。
图2为实施例1的化合物I晶型A的TGA图和DSC图叠图。
图3为布瓦西坦晶型C的XRPD图。
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施；所述化合物I通过专利WO2016191435方法制备。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
本发明所述的X射线粉末衍射图在PANalytical Empyrean X衍射粉末衍射仪上采集。
XRPD扫描参数Start Position[°2Th.]:3.0056；End Position[°2Th.]:39.9906；Step Size[°2Th.]:0.0167；Scan Step Time[s]:17.8500；K-Alpha1
Figure PCTCN2018075177-appb-000006
1.54060；K-Alpha2
Figure PCTCN2018075177-appb-000007
1.54443；电压:40mA；电流：45kV。
本发明所述差示扫描量热分析(DSC)图在TA Q200上采集。本发明所述差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述热重分析(TGA)图在TA Q500上采集。本发明所述热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
实施例1
化合物I晶型A的制备方法：
将30g化合物I(HPLC纯度为97.51％)加入180mL的四氢呋喃中，升温至60℃，搅拌0.5h，缓慢加入360mL正庚烷，缓慢降温至0～10℃，过滤，所得滤饼置于50℃真空烘箱内干燥过夜，所得固体经检测为晶型A，收率91％，HPLC纯度99.79％，手性HPLC纯度：化合物I为99.98％，化合物(R,S)-I未检测到，化合物(R,R)-I为0.01％，化合物(S,S)-I为0.01％。
本实施例得到的晶型A的XRPD数据如表1所示。
表1
2theta d间隔 相对强度％
7.85 11.26 100.00
13.94 6.35 2.46
15.68 5.65 15.15
17.39 5.10 2.74
19.07 4.65 1.71
21.73 4.09 6.50
25.47 3.49 2.30
28.04 3.18 3.36
28.61 3.12 20.76
36.49 2.46 1.94
实施例2
化合物I晶型A的制备方法：
将20g化合物I粉末(HPLC纯度为98.89％)加入120mL的四氢呋喃中，升温至60℃，搅拌0.5h，缓慢加入120mL正庚烷，缓慢降温至0～10℃，过滤，所得滤饼置于50℃真空烘箱内干燥过夜，所得固体经检测为晶型A，收率80％，HPLC纯度99.85％，手性HPLC纯度：化合物I为99.95％，化合物(R,S)-I未检测到，化合物(R,R)-I未检测到，化合物(S,S)-I为0.05％。
本实施例得到的晶型A的XRPD数据如表2所示。
表2
2theta d间隔 相对强度％
7.86 11.24 100.00
13.96 6.34 6.68
15.69 5.64 22.26
17.41 5.09 7.03
19.10 4.64 6.85
21.76 4.08 25.65
25.52 3.49 10.53
28.08 3.18 13.41
28.64 3.11 50.91
36.54 2.46 6.21
实施例3
化合物I晶型A的制备方法：
将1.28kg化合物I粉末(HPLC纯度为97.63％)加入7.7L的四氢呋喃中，升温至60℃，搅拌0.5h，缓慢加入15.4L正庚烷，缓慢降温至0～10℃，过滤，所得滤饼置于50℃真空烘箱内干燥过夜，所得固体经检测为晶型A，收率82％，HPLC纯度99.00％，手性HPLC纯度：化合物I为99.95％，化合物(R,S)-I未检测到，化合物(R,R)-I为0.03％，化合物(S,S)-I为0.02％。
本实施例得到的晶型A的XRPD数据如表3所示。
表3
2theta d间隔 相对强度％
7.86 11.24 100.00
13.95 6.34 4.93
15.69 5.64 17.53
17.40 5.09 5.13
19.08 4.64 4.22
21.75 4.08 16.26
25.49 3.49 5.88
28.06 3.17 8.20
28.62 3.11 35.43
36.51 2.46 3.11
实施例4
化合物I重结晶方法：
将500mg化合物I粉末(HPLC纯度为95.70％)加入4.5mL的丙酮中，升温至50℃，搅拌0.5h，缓慢加入6mL甲基环己烷，缓慢降温至0～10℃，过滤，所得滤饼置于50℃真空烘箱内干燥过夜，收率56.2％，HPLC纯度97.48％。
实施例5
化合物I重结晶方法：
将500mg化合物I粉末(HPLC纯度为95.70％)加入4.5mL的丙酮中，升温至50 ℃，搅拌0.5h，缓慢加入6mL正庚烷，缓慢降温至0～10℃，过滤，所得滤饼置于50℃真空烘箱内干燥过夜，收率57.5％，HPLC纯度96.29％。
实施例6
化合物I重结晶方法：
将500mg化合物I粉末(HPLC纯度为95.70％)加入4.5mL的丙酮中，升温至50℃，搅拌0.5h，缓慢加入4mL甲基叔丁基醚，缓慢降温至0～10℃，过滤，所得滤饼置于50℃真空烘箱内干燥过夜，收率51.2％，HPLC纯度95.73％。
实施例7
化合物I重结晶方法：
将500mg化合物I粉末(HPLC纯度为95.70％)加入3mL的四氢呋喃中，升温至60℃，搅拌0.5h，缓慢加入5mL甲基环己烷，缓慢降温至0～10℃，过滤，所得滤饼置于50℃真空烘箱内干燥过夜，收率63.4％，HPLC纯度96.59％。
实施例8
化合物I重结晶方法：
将500mg化合物I粉末(HPLC纯度为95.70％)加入3mL的四氢呋喃中，升温至60℃，搅拌0.5h，缓慢加入5mL甲基叔丁基醚，缓慢降温至0～10℃，过滤，所得滤饼置于50℃真空烘箱内干燥过夜，收率56.8％，HPLC纯度95.67％。
实施例9
化合物I重结晶方法：
将500mg化合物I粉末(HPLC纯度为95.70％)加入4.5mL的乙腈中，升温至60℃，搅拌0.5h，缓慢加入6mL水，缓慢降温至0～10℃，过滤，所得滤饼置于50℃真空烘箱内干燥过夜，收率75.8％，HPLC纯度96.68％。
实施例10
化合物I重结晶方法：
将500mg化合物I粉末(HPLC纯度为95.70％)加入4.5mL的丙酮中，升温至50℃，搅拌0.5h，缓慢加入6mL水，缓慢降温至0～10℃，过滤，所得滤饼置于50℃真 空烘箱内干燥过夜，收率80.5％，HPLC纯度95.70％。
实施例11
将500mg化合物I(手性HPLC中(S，S)异构体为0.60％)加入3mL的四氢呋喃中，升温至60℃，搅拌0.5h，缓慢加入6mL正庚烷，缓慢降温至0～10℃，过滤，所得滤饼置于50℃真空烘箱内干燥过夜，所得固体经检测为晶型A，收率90.7％，化合物(S,S)-I为0.20％。
实施例12
将500mg化合物I(手性HPLC中(S，S)异构体为0.33％)加入3mL的四氢呋喃中，升温至60℃，搅拌0.5h，缓慢加入6mL正庚烷，缓慢降温至0～10℃，过滤，所得滤饼置于50℃真空烘箱内干燥过夜，所得固体经检测为晶型A，收率92.5％，化合物(S,S)-I为0.14％。
实施例13
布瓦西坦晶型C的制备方法：
将240g布瓦西坦粉末(HPLC纯度为98.95％(R,R)+(S,S)异构体为0.23％)加入1.2L的甲基叔丁基醚，升温至50℃溶解完全，搅拌0.5h，缓慢降温至0～10℃，过滤，所得滤饼置于35℃真空烘箱内干燥过夜，所得固体经检测为晶型C，(HPLC纯度为99.75％，手性HPLC纯度为99.91％，(R,R)+(S,S)异构体为0.09％，(R,S)异构体未检测到)。
本实施例得到的晶型C的XRPD数据如表4所示。
表4
2theta d间隔 相对强度％
8.90 9.93 100.00
10.05 8.80 3.21
15.03 5.89 6.31
15.74 5.62 4.46
17.35 5.10 4.06
17.85 4.96 4.33
19.17 4.62 15.55
21.61 4.11 12.67
24.98 3.56 5.03
26.90 3.31 4.37

Claims (29)

  1. 一种化合物I的晶型A，其特征在于，其X射线粉末衍射图在2theta值为7.9°±0.2°，15.7°±0.2°，21.7°±0.2°,28.6°±0.2°处具有特征峰，
    其中化合物I的结构为，
    Figure PCTCN2018075177-appb-100001
  2. 根据权利要求1所述的晶型A，其特征在于，其X射线粉末衍射图还在2theta值为17.4°±0.2°，25.5°±0.2°，28.1°±0.2°处具有特征峰。
  3. 根据权利要求1或2所述的晶型A，其特征在于，其X射线粉末衍射图还在2theta值为14.0°±0.2°，19.1°±0.2°，36.5°±0.2°处具有特征峰。
  4. 根据权利要求1所述的晶型A，其特征在于，其X射线粉末衍射图基本与图1一致。
  5. 根据权利要求1所述的晶型A，其特征在于，其纯度大于98.0％。
  6. 根据权利要求5所述的晶型A，其特征在于，其纯度大于99.0％。
  7. 根据权利要求6所述的晶型A，其特征在于，其纯度大于99.5％。
  8. 根据权利要求1所述的晶型A，其特征在于，所述化合物I中，其对映及非对映异构体的含量均不大于2.5％，
    其中化合物I的对映异构体的结构为
    Figure PCTCN2018075177-appb-100002
    化合物I的非对映异构体包括如下结构式所示物质：
    Figure PCTCN2018075177-appb-100003
  9. 根据权利要求8所述的晶型A，其特征在于，其对映和非对映异构体的含量均不大于1.0％。
  10. 根据权利要求9所述的晶型A，其特征在于，其对映和非对映异构体的含量均不大于0.5％。
  11. 根据权利要求10所述的晶型A，其特征在于，其对映和非对映异构体的含量均不大于0.15％。
  12. 一种如权利要求1至11中任一项所述的化合物I的晶型A的制备方法，其特征在于：包括将化合物I粉末加入到一种或多种溶剂的混合体系中，进行结晶得到。
  13. 根据权利要求12所述的制备方法，其特征在于，所述结晶的方法包括混悬搅拌法，加热降温法，挥发法或反溶剂添加法。
  14. 根据权利要求12所述的制备方法，其特征在于，所述溶剂为选自水，醇类溶剂，醚类溶剂，酮类溶剂，酯类溶剂，芳香烃溶剂，卤代烃溶剂，腈类溶剂，硝基烷烃溶剂，脂肪烃类溶剂中的一种或几种。
  15. 根据权利要求14所述的制备方法，其特征在于，所述溶剂是醚类溶剂与脂肪烃类溶剂的混合体系，优选四氢呋喃与正庚烷的混合体系。
  16. 根据权利要求12所述的制备方法，其特征在于，所述结晶的方法为加热降温法，具体实施过程包括：将化合物I粉末加入到第一溶剂中，升温至50～60℃，搅拌，然后加入第二溶剂，降温至0～10℃，过滤，所得滤饼经干燥得到所述的晶型A，其中，所述的第一溶剂为水，醇类，醚类，酮类，酯类，芳香烃，卤代烃，腈类，硝基烷烃，脂肪烃类溶剂中的一种或几种的混合体系；所述的第二溶剂为水，醇类，醚类，酮类，酯类，芳香烃，卤代烃，腈类，硝基烷烃，脂肪烃类溶剂中的一种或几种的混合体系，所述的第一溶剂和所述的第二溶剂为不同的溶剂。
  17. 根据权利要求16所述的制备方法，其特征在于，所述的第一溶剂为醚类、酮类、腈类中的一种或几种的混合体系；所述的第二溶剂为脂肪烃类、醚类、水中的一种或几种的混合体系。
  18. 根据权利要求17所述的制备方法，其特征在于，所述的第一溶剂为四氢呋喃、丙酮、乙腈中的一种或几种的混合体系；所述的第二溶剂为正庚烷、甲基环己烷、甲基叔丁基醚、水中的一种或几种的混合体系。
  19. 一种如权利要求1至11中任一项所述的化合物I的晶型A作为中间体用于合成布瓦西坦的用途。
  20. 一种布瓦西坦的晶型C，其特征在于，其X射线粉末衍射图在2theta值为15.7°±0.2°,17.4°±0.2°，17.9°±0.2°,26.9°±0.2°处具有特征峰。
  21. 根据权利要求20所述的晶型C，其特征在于，其X射线粉末衍射图还在2theta值为8.9°±0.2°,19.2°±0.2°，21.6°±0.2°处具有特征峰。
  22. 根据权利要求20或21所述的晶型C，其特征在于，其X射线粉末衍射图还在2theta值为10.0°±0.2°,15.0°±0.2°，25.0°±0.2°处具有特征峰。
  23. 根据权利要求20所述晶型C，其特征在于，其X射线粉末衍射图基本上与图1一致。
  24. 一种如权利要求20至23中任一项所述的布瓦西坦晶型C的制备方法，其特征在于，包括将布瓦西坦粉末加入到一种或多种溶剂的混合体系中，进行结晶得到。
  25. 根据权利要求24所述的制备方法，其特征在于，所述结晶的方法包括混悬搅拌法，加热降温法，挥发法或反溶剂添加法。
  26. 根据权利要求24所述制备方法，其特征在于，所述溶剂为选自醇类溶剂，醚类溶剂，酮类溶剂，酯类溶剂，芳香烃溶剂，卤代烃溶剂，腈类溶剂，硝基烷烃溶剂，脂肪烃类溶剂中的一种或几种的混合体系。
  27. 根据权利要求26所述的制备方法，其特征在于，所述溶剂是甲基叔丁基醚。
  28. 一种药用组合物，所述药用组合物包含有效量的权利要求20至23中任一项所述的布瓦西坦的晶型C及药学上可接受的赋形剂。
  29. 如权利要求20至23中任一项所述的布瓦西坦的晶型C或如权利要求28所述的药物组合物用于制备治疗癫痫的药物制剂的用途。
PCT/CN2018/075177 2017-02-05 2018-02-03 布瓦西坦中间体的晶型a及其制备方法和布瓦西坦的晶型c及其制备方法 Ceased WO2018141276A1 (zh)

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CN111943880A (zh) * 2019-05-14 2020-11-17 浙江京新药业股份有限公司 一种布瓦西坦晶体及其制备方法和应用

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